Synthesis of nicotinonitrile derivatives as a new class of NLO materials

Article abstract of DOI:10.1016/S0040-4020(03)00507-6

4,6-Diaryl-2-(pyrrolidin-1-yl)-nicotinonitriles 2a-k and 3-amino-2,4-dicyano-5-aryl-biphenyls 3a-c were synthesized from 1,3-diaryl-prop-2-en-1-ones 1a-k and malononitrile by a convenient one-pot method. Likewise, the reaction of aromatic aldehydes with malononitrile afforded 6-amino-4-aryl-2-(pyrrolidin-1-yl)-pyridine-3,5-dicarbonitriles 6a-f. The reaction of mesityl oxide with malononitrile gave 5-amino-7- (pyrrolidin-1-yl)-2,4,4-trimethyl-1,4-dihydro-1,6-naphthyridine-8- carbonitrile 8. The NLO studies of the pyridinedinitrile derivatives 6a, b, f showed a high value while that of nicotinonitrile 2b was weak.

Full text of DOI:10.1016/S0040-4020(03)00507-6

Tetrahedron 59 (2003) 3761–3768
Synthesis of nicotinonitrile derivatives
as a new class of NLO materials
c
b,c
V. Raghukumar,a D. Thirumalai,a V. T. Ramakrishnan,a V. Karunakara and P. Ramamurthy
,
*
aDepartment of Organic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India
bDepartment of Inorganic Chemistry, University of Madras, Guindy Campus, Chennai 600 025, India
cNational Centre for Ultrafast Processes, University of Madras, Taramani Campus, Chennai 600 113, India
Received 22 January 2003; revised 4 March 2003; accepted 27 March 2003
Abstract—4,6-Diaryl-2-(pyrrolidin-1-yl)-nicotinonitriles 2a–k and 3-amino-2,4-dicyano-5-aryl-biphenyls 3a–c were synthesized from
1,3-diaryl-prop-2-en-1-ones 1a–k and malononitrile by a convenient one-pot method. Likewise, the reaction of aromatic aldehydes with
malononitrile afforded 6-amino-4-aryl-2-(pyrrolidin-1-yl)-pyridine-3,5-dicarbonitriles 6a–f. The reaction of mesityl oxide with
malononitrile gave 5-amino-7-(pyrrolidin-1-yl)-2,4,4-trimethyl-1,4-dihydro-1,6-naphthyridine-8-carbonitrile 8. The NLO studies of the
pyridinedinitrile derivatives 6a, b, f showed a high value while that of nicotinonitrile 2b was weak. q 2003 Elsevier Science Ltd. All rights
reserved.
1. Introduction
report a simple, one-pot synthesis of nicotinonitriles,
pyridinedinitriles and biaryl derivatives as well as the 1,4-
dihydro-1,6-naphthyridine system.
The pyridine ring is one of the most well known systems
among the naturally occurring heterocycles.1 Pyridine and
fused pyridine moieties are present in numerous natural
products such as quinoline and isoquinoline alkaloids,2 and
nicotine and its analogues.3–5 They have a vast range of
potential biological activities as herbicides6 and have been
used for enrichment of cereals,7 and for regulation of arterial
pressure8 and cholesterol levels in blood.9 Some polysub-
stituted pyridines are used as non-linear optical materials,10
electrical materials,11 chelating agents in metal–ligand
chemistry12 and as fluorescent liquid crystals.13 Thus
pyridine derivatives have become increasingly important
and hence numerous synthetic methods of pyridine rings
have been reviewed.14 – 17 The formation of pyridine
compounds from a,b-unsaturated ketones and malononitrile
in the presence of ammonium acetate has been reported.18
The reaction of b-aminoenones with malononitrile, furnish-
ing 2(1H)-pyridinones (pyridones), is known.19 Photoche-
mical synthesis of 2-aryl and 2,6-diaryl pyridines have also
been reported.20 In continuation of our work on the
synthesis of laser dyes21 – 23 and non-linear optical
materials,24 we have reported the synthesis of 1,6-
naphthyridine25 and terphenyl26 systems, from a,b-unsatu-
rated ketones and malononitrile; the formation of these
compounds varied according to the experimental con-
ditions, depending upon the amount of malononitrile and
pyrrolidine, which were used for the reaction. Herein, we
2. Results and discussion
The reaction of enones 1a–k, (Table 1) with 1 equiv. each
of malononitrile and pyrrolidine in ethanol furnished the
nicotinonitriles 2a–k in 40–69% yields. The formation of
the nicotinonitriles could be rationalized by Michael
addition, enamine formation followed by condensation
and aromatization. The reaction of the thienyl and pyridyl
enones 1i–k with 2 equiv. each of malononitrile and
pyrrolidine in ethanol furnished the nicotinonitriles 2i–k
along with the thienyl/pyridyl substituted biphenyl deriva-
tives 3a–c (Scheme 1). When morpholine was used in place
Table 1. Reaction of enones 1a–k with malononitrile and pyrrolidine
1,2
3
R
Ar
a
b
c
d
e
f
g
h
i
–
–
–
–
–
–
–
–
a
b
c
CH3
OCH3
Cl
H
H
OCH3
OCH3
OCH3
H
CH3
H
4-NMe2–C6H4–
4-NMe2–C6H4–
4-NMe2–C6H4–
4-NMe2–C6H4–
4-NEt2–C6H4–
4-NEt2–C6H4–
C6H5–
4-OCH3–C6H4–
2-Thienyl
2-Thienyl
Keywords: pyridines; naphthyridines; electronic spectra.
*
j
k
Corresponding author. Tel.: þ91-44-2235-1269x213; fax: þ91-44-2235-
2-Pyridyl
2494; e-mail: vtrk28@yahoo.com
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00507-6

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V. Raghukumar et al. / Tetrahedron 59 (2003) 3761–3768
Scheme 1.
Scheme 2.
of pyrrolidine the respective morpholine derivative 4 was
obtained from the enone 1 l in 67% yield (Scheme 2). The
formation of the biphenyl ring system from enone on
reaction with 2 equiv. of malononitrile in the presence of a
catalytic amount of pyrrolidine has been reported earlier.26
aromatization (Scheme 3). The reaction of benzylidene
malononitrile with dimedone giving tetrahydrobenzopyran
derivative is reported.30
The IR spectrum of product 6c showed strong absorptions at
3475, 3345 cm21 due to amino group, and at 2206 cm21 due
1
The IR spectrum of compound 2b showed a strong
absorption band at 2194 cm21 due to cyano group. Proton
NMR spectrum of 2b showed a triplet for N-CH2–CH2 at d
2.02 (4H) and another triplet for N-CH2–CH2 at d 3.90
(4H). 13C NMR spectrum of the product 2b showed N-
CH2–CH2 carbons at d 25.94 (t) and N-CH2–CH2 carbon at
d 49.70 (t); the cyano group attached pyridine ring carbon
appeared at d 86.10 and the cyanocarbon appeared at d
114.15. Full data for all compounds are furnished in the
experimental section. The structures of 2c, 2f and 2g have
been confirmed by X-ray analysis.27–29
to cyano group. The H 0NMR spectrum of 6c showed a
triplet at d 1.94 due to 30,4 -CH2 and a triplet at d 3.75 for N-
CH2 protons in the pyrrolidine ring and a broad singlet at d
5.31 for the NH2 protons (exchanged with D2O). 13C NMR
spectrum of com0pound 6c showed aromatic methyl carbon
at d 21.42, the 3 , 40 methylene carbons of the pyrrolidine
moiety at d 25.36, the nitrogen attached methylene carbons
at d 49.51, the two cyano attached carbons at d 82.09 and
83.21, the two cyano carbons at d 116.88 and 118.31. 13C
NMR, recorded using DEPT-135 technique, showed two
inverted signals at d 25.36 (#) for N-CH2–CH2 and at d
49.51(#) for N-CH2–CH2 of the pyrrolidine ring. Similar
procedure furnished the other pyridinedinitriles 6a–f.
The biphenyl derivative 3b was characterized by spectral
data and analysis. The IR spectrum showed the amino
(3469, 3356 cm21) and cyano (2213 cm21) groups. The
proton NMR showed the NH2 at d 5.39 (exchanged by
D2O), p-tolyl moiety at d 2.43 (s), d 7.32 and d 7.47 (2d,
J¼8.3 Hz), the C6 proton at d 7.26 (s) and thienyl protons at
d 7.18, 7.50 and d 7.75.
The reaction of mesityloxide 7 with 2 equiv. each of
Table 2. Reaction of aromatic aldehydes 5a–f with malononitrile and
pyrrolidine
6
Ar
The reaction of aromatic aldehydes 5a–f, (Table 2) with
2 equiv. each of malononitrile and pyrrolidine in ethanol
afforded the pyridine dinitrile derivatives 6a–f, respect-
ively, in 41–56% yields. The formation of the pyridine ring
could be rationalized by Knoevenagel condensation,
Michael addition, enamine formation, cyclization and
a
b
c
d
e
f
4-Me2N–C6H4–
4-Et2N–C6H4–
4-CH3—C6H4–
4-CH3O–C6H4–
C6H5–
Indol-3-yl

V. Raghukumar et al. / Tetrahedron 59 (2003) 3761–3768
3763
Scheme 3.
Scheme 4.
We have reported the spectral and photophysical properties
of 1,6-naphthyridines derivatives as a new class of
compounds for non-linear optics. The NLO efficiency of
five 1,6-naphthyridine derivatives ranged from 51 to 91%
when compared with urea as standard.24 On the above lines,
we have studied the NLO properties of compounds 2b, 6a,
6b and 6f. The SHG efficiency of these compounds
compared to urea was examined by the Kurtz powder
technique using a Nd-YAG pulsed laser (1064 nm, 8 ns
pulse), following the experimental conditions described
earlier.24 The data is given in Table 3. Thus the present work
has shown that pyridinedinitrile system 6 is a new ring
system having better NLO efficiency (152–194%) com-
pared to the standard urea.
Table 3. SHG efficiency of pyridines
Compound No.
DmV (average)
SHG efficiency (%)
Urea
2b
6a
6b
6f
328.55
91.66
599.00
638.33
499.66
100
27.89
182.31
194.28
152.08
malononitrile and pyrrolidine, in ethanol afforded the 1,4-
dihydro-1,6-naphthyridine 8, in 32% yield (Scheme 4).
Thus, the lack of hydrogen in the b-position of the enone
resulted in the formation of the dihydro product 8, curtailing
the dehydrogenation step.25
The IR spectrum of compound 8 showed strong absorption
bands at 3492, 3352 and 3211 cm21 due to NH2, NH groups
and at 2179 cm21 due to cyano group. The proton NMR
spectrum of 8 showed a singlet at d 1.37 (6H) for gem-
dimethyl protons and a singlet at d 1.80 for the C-2 methyl
protons; a triplet at d 1.91 (4H) and another triplet at d 3.68
(4H) confirmed the pyrrolidine moiety; a singlet at d 4.21
for the C-3 attached proton, a broad singlet at 4.74 for NH2
protons (exchanged with D2O) and a broad singlet at d 5.91
for NH proton were also seen consistent with the structure of
8. Further, the structure of compound 8 was also confirmed
by X-ray crystallographic studies.31
3. Conclusions
Thus, the reaction of enone with malononitrile depended on
the number of equivalents of the malononitrile and the base
such as pyrrolidine, piperidine or morpholine used for the
reaction, leading to 1,6-naphthyridines and terphenyl/bi-
phenyl system; dihydronaphthyridine was obtained when b-
hydrogen was absent in the enone. The pyridinedinitriles 6a,
6b, 6f have been identified as efficient NLO compounds.
4. Experimental
4.1. General
2.1. Non-linear optical studies
The donor–acceptor substituted compounds have generated
interest in recent years since they exhibit unique photo-
physical, photochemical and optical properties due to
charge transfer interaction between the donor and acceptor
substituents. Recently several new classes of compounds
showing second harmonic generation (SHG) have been
studied.32,33
All melting points are uncorrected. IR spectra were recorded
on Shimadzu FT-IR 8300 model. 1H and 13C NMR spectra
were recorded on Brucker 300 MHz and Jeol GMX
400 MHz spectrometers with CDCl3 and DMSO-d6 as the
solvents with tetramethylsilane as the internal standard.
Mass spectra were taken on Hewlett–Packard 5985 (70ev)

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V. Raghukumar et al. / Tetrahedron 59 (2003) 3761–3768
instrument. Absorption spectra were recorded using Shi-
madzu UV 260 spectrophotometer. Column chromato-
graphy was performed on silica gel (100–200 mesh).
2198 (CN) cm21; 1H NMR: d 1.99 and 3.87 (2t, 8H, 30, 40-
CH2 and N-CH2, pyrrolidine), 3.01 (s, 6H, N(CH3)2), 6.77
(d, 2H, J¼8.8 Hz), 7.03 (s, 1H), 7.39 (d, 2H, J¼8.8 Hz),
7.59 (d, 2H, J¼8.8 Hz), 8.0 (d, 2H, J¼8.8 Hz). 13C NMR: d
25.64, 40.15, 49.46, 86.93, 108.55, 111.75, 119.68, 124.81,
128.24, 128.87, 129.70, 135.65, 137.01, 151.16, 156.27,
157.61, 158.59. MS: m/z (%)¼402 (50, Mþ2), 400 (98), 372
(80), 359 (50), 345 (100), 260 (10), 201 (12), 70 (38). Anal.
Calcd for C24H23N4Cl (402.92): C, 71.54; H, 5.75; N, 13.90.
Found: C, 71.52; H, 5.79; N, 13.86.
4.2. General procedure for the preparation of
nicotinonitriles 2a–k
To a solution of enone 1 in absolute ethanol (20 mL),
malononitrile (1 equiv.) was added dropwise, followed by
the addition of pyrrolidine/morpholine (1 equiv.) at room
temperature. The reaction mixture was refluxed on a water
bath until the disappearance of the starting material,
monitored by TLC; the solvent was removed and the
residue obtained was purified by column chromatography
using silica gel; elution with hexane/chloroform (1:1)
mixture afforded the corresponding nicotinonitrile 2; the
products were recrystallized from ethanol.
4.2.4. 4-(4-Dimethylaminophenyl)-6-phenyl-2-(pyrroli-
din-1-yl)-nicotinonitrile (2d). Following the above general
procedure, treatment of 3-(4-dimethylaminophenyl)-1-
phenyl-prop-2-en-1-one 1d (1.0 g, 3.98 mmol) with mal-
ononitrile (0.26 g, 3.94 mmol) and pyrrolidine (0.28 g,
3.94 mmol) in absolute ethanol on refluxing for 9 h, gave
the compound 2d. Yield: 0.65 g (46%), greenish yellow
4.2.1. 4-(4-Dimethylaminophenyl)-6-(4-methylphenyl)-2-
(pyrrolidin-1-yl)-nicotinonitrile (2a). Following the above
general procedure, treatment of 3-(4-dimethylaminophe-
solid, mp 180–1828C; IR (KBr): 2198 (CN) cm21 1H
;
NMR: d 2.00 and 3.91 (2t, 8H, J¼6.4 Hz, 30, 40-CH2 and N-
CH2, pyrrolidine), 3.01 (s, 6H, N(CH3)2), 6.79 (d, 2H,
J¼8.3 Hz), 7.12 (s, 1H), 7.43–7.57 (m, 5H, Ar-H), 8.06 (d,
2H, J¼8.2 Hz).13C NMR: d 25.60, 40.11, 49.40, 86.64,
108.80, 111.70, 119.78, 124.97, 127.09, 128.42, 129.28,
129.56, 138.53, 151.05, 157.37, 157.55, 158.65. MS: m/z
(%)¼368 (Mþ, 94), 340 (32), 339 (100), 323 (22), 276 (40),
169 (28). Anal. Calcd for C24H24N4 (368.47): C, 78.23; H,
6.57; N, 15.21. Found: C, 78.38; H, 6.64; N, 15.01.
nyl)-1-(4-methylphenyl)-prop-2-en-1-one
1a
(1.0 g,
3.77 mmol) with malononitrile (0.25 g, 3.78 mmol) and
pyrrolidine (0.27 g, 3.80 mmol) in absolute ethanol and
refluxing for 9 h, gave the compound 2a. Yield: 0.63 g
(44%), yellow solid, mp 164–1668C; IR (KBr0): 2198
0
1
(CN) cm21; H NMR: d 2.01 and 3.91 (2t, 8H, 3 ,4 -CH2
and N-CH2, pyrrolidine), 2.41 (s, 3H, CH3), 3.01 (s, 6H, N
(CH3)2), 6.79 (d, 2H, J¼8.7 Hz), 7.09 (s, 1H), 7.25 (d, 2H,
J¼7.9 Hz), 7.54 (d, 2H, J¼8.7 Hz), 7.98 (d, 2H, J¼7.9 Hz).
13C NMR: d 21.28, 25.64, 40.15, 49.41, 86.38, 108.58,
111.76, 119.89, 125.15, 127.06, 129.40, 129.68, 135.83,
139.75, 151.07, 157.29, 157.63, 158.71. MS: m/z (%)¼382
(Mþ, 30), 381 (94), 380 (100), 352 (96), 336 (24), 326 (22),
269 (14), 70 (32). Anal. Calcd for C25H26N4 (382.49): C,
78.49; H, 6.85; N, 14.64. Found: C, 78.72; H, 6.74; N, 14.83.
4.2.5. 4-(4-Diethylaminophenyl)-6-phenyl-2-(pyrrolidin-
1-yl)-nicotinonitrile (2e). Reaction of 3-(4-diethylamino-
phenyl)-1-phenyl-prop-2-en-1-one 1e (1.0 g, 3.58 mmol)
with malononitrile (0.24 g, 3.63 mmol) and pyrrolidine
(0.25 g, 3.52 mmol) in absolute ethanol on refluxing for 9 h,
gave the compound 2e. Yield: 0.62 g (44%), yellow solid,
1
mp 170–1728C; IR (KBr): 2191 (CN) cm21; H NMR: d
1.20 (t, 6H, N(CH2CH3)2), 1.99 and 3.86 (2t, 8H, 30, 40-CH2
and N-CH2, pyrrolidine), 3.40 (q, 4H, N(CH2CH3)2), 6.73
(d, 2H, J¼8.7 Hz), 7.04 (s, 1H), 7.37–7.52 (m, 5H, Ar-H),
7.55 (d, 2H, J¼8.5 Hz).13C NMR: d 12.54, 25.64, 44.28,
49.47, 86.80, 108.43, 110.97, 119.76, 23.67, 124.02, 128.66,
129.99, 131.59, 137.52, 148.65, 156.25, 157.58, 158.70.
MS: m/z (%)¼396 (Mþ, 4), 394 (14), 39 (100), 330 (18).
Anal. Calcd for C26H28N4 (396.54): C, 78.75; H, 7.11; N,
14.12. Found: C, 79.02; H, 6.94; N, 14.42.
4.2.2. 4-(4-Dimethylaminophenyl)-6-(4-methoxyphenyl)-
2-(pyrrolidin-1-yl)-nicotinonitrile (2b). Treatment of 3-
(4-dimethylaminophenyl)-1-(4-methoxyphenyl)-prop-2-en-
1-one 1b (0.5 g, 1.77 mmol) with malononitrile (0.12 g,
1.81 mmol) and pyrrolidine (0.13 g, 1.81 mmol) in absolute
ethanol under reflux for 9 h, afforded the compound 2b.
Yield: 0.45 g (64%), yellow solid, mp 182–1848C; IR
(KBr): 21940(CN) cm21; 1H NMR: d 2.02 and 3.90 (2t, 8H,
J¼6.6 Hz, 3 ,40-CH2 and N-CH2, pyrrolidine), 3.02 (s, 6H,
N(CH3)2), 3.87 (s, 3H), 6.82 (d, 2H, J¼8.7 Hz), 6.96 (d, 2H,
J¼8.7 Hz), 7.04 (s, 1H), 7.54 (d, 2H, J¼8.7 Hz), 8.04 (d,
2H, J¼8.7 Hz). 13C NMR: d 25.94, 40.46, 49.70, 55.56,
86.10, 108.50, 112.10, 114.15, 120.23, 125.60, 128.89,
129.95, 131.53, 151.41, 157.58, 159.04, 161.32; 13C NMR
(DEPT-135): d 25.94(#), 49.70(#). MS: m/z (%)¼398 (Mþ,
62), 397 (84), 370 (20), 369 (100), 355 (10), 326 (16), 298
(8), 70 (36). Anal. Calcd for C25H26N4O (398.52): C, 75.34;
H, 6.57; N, 14.05. Found: C, 74.94; H, 6.63; N, 13.75.
4.2.6. 4-(4-Diethylaminophenyl)-6-(4-methoxyphenyl)-2-
(pyrrolidin-1-yl)-nicotinonitrile (2f). Treatment of 3-(4-
diethylaminophenyl)-1-(4-methoxyphenyl)-prop-2-en-1-
one 1f (1.0 g, 3.23 mmol) with malononitrile (0.21 g,
3.18 mmol) and pyrrolidine (0.23 g, 3.23 mmol) in absolute
ethanol under reflux for 9 h, gave the compound 2f. Yield:
0.58 g (41%), yellow solid, mp 208–2108C; IR (KBr): 2191
1
(CN) cm21; H NMR: d 1.20 (t, 6H, N (CH2CH3)2), 1.99
and 3.87 (2t, 8H, J¼6.6 Hz, 30, 40-CH2 and N-CH2,
pyrrolidine), 3.39 (q, 4H, N(CH2CH3)2), 3.84 (s, 3H,
OCH3), 6.73 (d, 2H, J¼8.8 Hz), 6.96 (d, 2H, J¼8.8 Hz),
7.06 (s, 1H), 7.53 (d, 2H, J¼8.8 Hz), 8.03 (d, 2H,
J¼8.8 Hz). 13C NMR: d 12.52, 25.64, 44.25, 49.41, 55.24,
85.77, 108.04, 110.94, 113.80, 120.07, 124.07, 128.55,
129.67, 131.20, 148.51, 157.14, 157.19, 158.82, 160.94.
Anal. Calcd for C27H30N4O (426.57): C, 76.03; H, 7.08; N,
13.13. Found: C, 75.92; H, 7.11; N, 13.47.
4.2.3. 6-(4-Chlorophenyl)-4-(4-dimethylaminophenyl)-2-
(pyrrolidin-1-yl)-nicotinonitrile (2c). Treatment of 1-(4-
chlorophenyl)-3-(4-dimethylaminophenyl)-prop-2-en-1-
one 1c (1.0 g, 3.50 mmol) with malononitrile (0.23 g,
3.48 mmol) and pyrrolidine (0.25 g, 3.52 mmol) in ethanol
under reflux for 10 h, gave the compound 2c. Yield: 0.69 g
(49%), greenish yellow solid, mp 180–1828C; IR (KBr):

V. Raghukumar et al. / Tetrahedron 59 (2003) 3761–3768
3765
4.2.7. 6-(4-Methoxyphenyl)-4-phenyl-2-(pyrrolidin-1-
yl)-nicotinonitrile (2g). Following the above general
procedure, treatment of 1-(4-methoxyphenyl)-3-phenyl-
prop-2-en-1-one 1g (0.5 g, 2.10 mmol) with malononitrile
(0.14 g, 2.12 mmol) and pyrrolidine (0.15 g, 2.11 mmol) in
absolute ethanol and refluxing for 9 h, gave the compound
2g. Yield: 0.51 g (69%), pale yellow solid, mp 168–1708C;
IR (KBr): 2200 (CN) cm21; 1H NMR: d 2.00 and 3.90 (2t,
8H, J¼6.3 Hz, 30, 40-CH2 and N-CH2 pyrrolidine), 3.86 (s,
3H, OCH3), 6.96 (d, 2H, J¼8.8 Hz), 7.02 (s, 1H), 7.46–7.57
(m, 5H, Ar-H), 8.03 (d, 2H, J¼8.8 Hz). 13C NMR: d 25.55,
49.28, 55.22, 86.28, 108.44, 113.84, 119.20, 128.32, 128.36,
128.43, 129.08, 130.69, 138.06, 157.16, 157.52, 158.05,
161.15. MS: m/z (%)¼355 (Mþ, 32), 354 (68), 32 (60), 70
(100). Anal. Calcd for C23H21N3O (355.44): C, 77.72; H,
5.95; N, 11.82. Found: C, 77.70; H, 5.92; N, 11.79.
108.62, 119.49, 127.17, 127.81, 128.08, 128.85, 129.36,
135.38, 139.03, 140.30, 148.70, 158.32, 158.79. MS (%):
m/z 344 (Mþ-1, 20), 288 (14), 263 (23), 183 (28), 165 (17),
137 (27), 123 (29), 116 (17), 111 (36), 106 (73), 98 (34), 97
(62), 85 (54), 83 (64), 81 (49), 71 (34), 70 (61). Anal. calcd
for C21H19N3S (345.47): C, 73.01; H, 5.54; N, 12.16. Found:
C, 72.75, H, 5.45; N, 12.02.
4.2.11. 6-Phenyl-4-(2-pyridyl)-2-(pyrrolidin-1-yl)-nicoti-
nonitrile (2k). Following the above general procedure,
treatment of 1-phenyl-3-(2-pyridyl)-prop-2-en-1-one 1k
(1 g, 4.78 mmol) with malononitrile (0.32 g, 4.84 mmol)
and pyrrolidine (0.34 g, 4.78 mmol) in absolute ethanol and
refluxing for 9 h, gave the compound 2k. Yield: 0.82 g
(52%), yellowish orange solid, mp 152–1548C; IR (KBr):
1
2197 (CN), 1547, 1546, 1483, 1245, 776,0 761 cm21; H
NMR (CDCl3, 300 MHz): d 2.03 (bs, 4H, 3 and 40-CH2 in
pyrrolidine), 3.94 (t, 4H, J¼6.0 Hz, N-CH2 in pyrrolidine),
7.26 (s, 1H, C5-Ar H), 7.35–7.49 (m, 4H), 7.74–7.87 (m,
2H), 8.09–8.12 (m, 2H), 8.78–8.80 (d, 1H, J¼4.8 Hz); 13C
NMR (CDCl3, 75 MHz): d 25.64, 49.47, 86.59, 109.02,
118.88, 123.84, 123.90, 127.30, 128.55, 129.97, 136.66,
138.14, 149.85, 155.40, 155.45, 158.21, 158.39. MS (%):
m/z 326 (Mþ, 100), 325 (27), 298 (32), 297 (83), 271 (11),
257 (13), 256 (16), 229 (13), 102 (7), 71 (7), 70 (32). Anal.
calcd for C21H18N4 (326.40): C, 77.28; H, 5.56; N, 17.16.
Found: C, 76.95, H, 5.41; N, 17.02.
4.2.8. 4,6-Di-(4-methoxyphenyl)-2-(pyrrolidin-1-yl)-
nicotinonitrile (2h). Reaction of 1,3-di-(4-methoxy-
phenyl)-prop-2-en-1-one 1h (0.5 g, 1.86 mmol) with mal-
ononitrile (0.12 g, 1.82 mmol) and pyrrolidine (0.13 g,
1.83 mmol) in absolute ethanol under reflux for 9 h, gave
the compound 2h. Yield: 0.31 g (43%), brownish yellow
solid, mp 174–1768C; IR (KBr): 2202 (CN) cm21 1H
;
NMR: d 2.00 and 3.90 (2t, 8H, 30, 40-CH2 and N-CH2,
pyrrolidine), 3.85 and 3.87 (2 s, 6H, (OCH3)2), 6.96 (d, 2H,
J¼8.8 Hz), 7.03 (s, 1H), 7.26 (d, 2H, J¼8.8 Hz), 7.52 (d,
2H, J¼8.8 Hz), 8.03 (d, 2H, J¼8.8 Hz). Anal. Calcd for
C24H23N3O2 (385.46): C, 74.78; H, 6.01; N, 10.90. Found:
C, 74.57; H, 6.32; N, 11.14.
4.2.12. 4-(2-Chlorophenyl)-6-(4-methylphenyl)-2-(mor-
pholin-1-yl)-nicotinonitrile (4). Following the above gen-
eral procedure, treatment of 3-(2-chlorophenyl)-1-(4-
methylphenyl)-prop-2-en-1-one 1l (0.5 g, 1.95 mmol) with
malononitrile (0.13 g, 1.96 mmol) and morpholine (0.17 g,
1.95 mmol) in absolute ethanol and refluxing for 9 h, gave
the compound 4. Yield: 0.52 g (67%), pale yellow solid, mp
4.2.9. 6-Phenyl-4-(2-thienyl)-2-(pyrrolidin-1-yl)-nicoti-
nonitrile (2i). Following the above general procedure,
treatment of 1-phenyl-3-(2-thienyl)-prop-2-en-1-one 1i
(1 g, 4.67 mmol) with malononitrile (0.31 g, 4.67 mmol)
and pyrrolidine (0.33 g, 4.67 mmol) in absolute ethanol and
refluxing for 9 h, gave the compound 2i. Yield: 0.80 g
(51%), brownish yellow solid, mp 120–1228C; IR (KBr):
2200 (CN), 1562, 1541, 1424, 690 cm21; 1H NMR (CDCl3,
300 MHz): d 2.03 (t, 4H, J¼6.6 Hz, 30, 40-CH2 in
pyrrolidine), 3.92 (t, 4H, J¼6.6 Hz, N-CH2 in pyrrolidine),
7.26 (s, 1H, C5-Ar H), 7.18–8.08 (m, 8H, Ar-H); 13C NMR
(CDCl3, 100 MHz): d 25.69, 49.63, 108.90, 119.41, 127.25,
127.94, 128.13, 128.63, 128.79, 128.94, 130.05, 138.15,
138.80, 148.84, 158.34. MS (%): m/z 331 (Mþ, 59), 330
(89), 304 (9), 302 (100), 276 (17), 262 (9), 261 (16), 165
(Mþþ, 10), 102 (6), 70 (23). Anal. calcd for C20H17N3S
(331.44): C, 72.42; H, 5.17; N, 12.69. Found: C, 72.20, H,
5.02; N, 12.45.
262–2648C; IR (KBr): 2194 (CN) cm21
;
1H NMR
(300 MHz): d 2.17 (s, 3H, CH3), 3.31 (t, 4H), 3.58 (t, 4H),
7.02–7.25 (m, 7H, Ar-H), 7.53 (d, 2H, J¼7.9 Hz); 13C
NMR: d 20.73, 48.59, 66.14, 114.21, 116.80, 117.61,
123.42, 126.13, 127.64, 129.53, 130.35, 131.47, 136.36,
138.01, 138.36, 147.71, 153.84, 156.89, 165.99. Anal. calcd
for C23H20N3OCl (389.88): C, 70.85; H, 5.17; N, 10.77.
Found: C, 71.02; H, 5.20; N, 11.08.
4.3. General procedure for the preparation of biphenyls
3a–c
To a solution of enone 1 in absolute ethanol (20 mL),
malononitrile (2 equiv.) was added dropwise, followed by
the addition of pyrrolidine (2 equiv.) at room temperature.
Then, the reaction mixture was refluxed on a water bath for
10–12 h and the solvent was removed. The residue obtained
was purified by column chromatography using silica gel and
eluted with hexane/ethyl acetate (3:2) mixture to afford
biphenyls 3a–c along with nicotinonitriles 2i–k, the latter
were identified by comparison with the above prepared
samples.
4.2.10. 6-(4-Methylphenyl)-4-(2-thienyl)-2-(pyrrolidin-1-
yl)-nicotinonitrile (2j). Following the above general
procedure, treatment of 1-(4-methylphenyl)-3-(2-thienyl)-
prop-2-en-1-one 1j (1 g, 4.38 mmol) with malononitrile
(0.29 g, 4.39 mmol) and pyrrolidine (0.31 g, 4.36 mmol) in
absolute ethanol and refluxing for 10 h, gave the compound
2j. Yield: 0.82 g (54%), yellow solid, mp 130–1328C; IR
(KBr): 2199 (CN), 1561, 1541, 1508, 1424, 809, 706 cm21
;
1H NMR (CDCl3, 300 MHz): d 2.02 (bs, 4H, 30 and 40-CH2
in pyrrolidine), 2.42 (s, 3H, Ar-CH3), 3.91 (t, 4H, J¼5.8 Hz,
N-CH2 in pyrrolidine), 7.17 (s, 1H, C5-Ar H), 7.28–7.6 (m,
4H), 7.72 (d, 1H, J¼1.8 Hz), 7.96 (d, 2H, J¼7.0 Hz); 13C
NMR (CDCl3, 75 MHz): d 21.38, 25.68, 49.58, 85.34,
4.3.1. 3-Amino-2,4-dicyano-5-(2-thienyl)-biphenyl (3a).
Following the above general procedure, treatment of 1-
phenyl-3-(2-thienyl)-prop-2-en-1-one 1i (1 g, 4.67 mmol)
with malononitrile (0.62 g, 9.39 mmol) and pyrrolidine
(0.66 g, 9.29 mmol) in absolute ethanol and refluxing for

3766
V. Raghukumar et al. / Tetrahedron 59 (2003) 3761–3768
12 h, gave the compounds 2i (yield: 0.49 g (32%)) and 3a.
Yield: 0.69 g (49%), yellow solid, mp 238–2408C; IR
(KBr): 3474, 3375 (NH2), 2211 (CN), 1634, 1572, 1421,
1286, 718, 696 cm21; 1H NMR (CDCl3, 400 MHz): d 5.41
(bs, 2H, NH2), 7.00 (s, 1H, C6-Ar H), 7.2 (2d, 1H, J¼5.0 and
3.6 Hz), 7.50–7.60 (m, 6H), 7.75–7.76 (2d, 1H, J¼3.7 and
1.2 Hz); 13C NMR (CDCl3, 100 MHz): d 93.00, 94.64,
115.88, 116.27, 119.34, 128.34, 128.49, 128.78, 128.93,
129.77, 137.22, 138.68, 141.72, 150.19, 153.52. MS (%):
m/z 301 (Mþ, 57), 300 (M-1, 100), 273 (14), 272 (9), 255
(7), 228 (6), 150 (11), 136 (12), 88 (6), 77 (4). Anal. calcd
for C18H11N3S (301.38): C, 71.74; H, 3.68; N, 13.94. Found:
C, 71.48, H, 3.62; N, 13.75.
pressure. The residue was purified by column chromato-
graphy using silica gel and eluted with hexane/chloroform
(1:1) to furnish the corresponding polysubstituted pyridine
derivative 6.
4.4.1. 6-Amino-4-(4-dimethylaminophenyl)-2-(pyrroli-
din-1-yl)-pyridine-3,5-dicarbonitrile (6a). Following the
above general procedure, treatment of 4-dimethylamino-
benzaldehyde 5a (0.75 g, 5.03 mmol) with malononitrile
(0.66 g, 10 mmol) and pyrrolidine (0.71 g, 10 mmol) in
absolute ethanol under reflux for 10 h, furnished the
compound 6a. Yield: 0.92 g (55%), yellow solid, mp
252–2548C; IR (KBr): 3454, 3340 (NH2), 2200
1
(CN) cm21; H NMR: d 1.97 and 4.11 (2t, 8H, J¼6.6 Hz,
4.3.2. 3-Amino-2,4-dicyano-40-methyl-5-(2-thienyl)-
biphenyl (3b). Following the above general procedure,
treatment of 1-(4-methylphenyl)-3-(2-thienyl)-prop-2-en-1-
one 1j (1 g, 4.38 mmol) with malononitrile (0.58 g,
8.78 mmol) and pyrrolidine (0.62 g, 8.73 mmol) in absolute
ethanol and refluxing for 11 h, gave the compounds 2j
(yield: 0.40 g (26%)) and 3b. Yield: 0.69 g (50%), greenish
yellow solid, mp 180–1828C; IR (KBr): 3469, 3356 (NH2),
30, 40 CH2 and N-CH2, pyrrolidine), 3.02 (s, 6H, N(CH3)2),
5.28 (bs, 2H, exchanged with D2O), 6.76 (d, 2H, J¼9.0 Hz),
7.43 (d, 2H, J¼9.0 Hz).13C NMR: d 25.44, 40.06, 49.58,
80.48, 81.36, 111.43, 117.68, 119.01, 121.59, 130.09,
151.62, 158.20, 159.66, 162.15. MS: m/z (%)¼332 (Mþ,
100), 331 (62), 303 (34), 287 (16), 260 (31), 219 (21), 151
(28), 70 (21). Anal. Calcd for C19H20N6 (332.41): C, 68.65;
H, 6.06; N, 25.25. Found: C, 68.91; H, 6.24; N, 25.03.
1
2213 (CN), 1621, 1595, 1541, 813, 696 cm21; H NMR
(CDCl3, 400 MHz): d 2.43 (s, 3H, CH3), 5.39 (bs, 2H, NH2),
7.18 (2d, 1H, J¼4.9 and 3.9 Hz), 7.26 (s, 1H, C6-Ar H),
7.32–7.47 (2d, 4H, J¼8.30 Hz), 7.50 and 7.75 (2d, 2H); 13C
NMR (CDCl3, 100 MHz): d 21.35, 93.00, 95.00, 116.07,
116.35, 119.24, 128.22, 128.47, 128.70, 129.62, 134.33,
138.76, 140.06, 141.61, 150.25, 153.54. MS (%): m/z 315
(Mþ, 100), 314 (M-1, 26), 300 (6), 288 (9), 287 (13), 231
(3), 156.7 (Mþþ, 9), 91 (7), 77 (3). Anal. calcd for
C19H13N3S (315.40): C, 72.36; H, 4.15; N, 13.32. Found: C,
72.30, H, 4.11; N, 13.18.
4.4.2. 6-Amino-4-(4-diethylaminophenyl)-2-(pyrrolidin-
1-yl)-pyridine-3,5-dicarbonitrile (6b). Following the
above general procedure, treatment of 4-diethylamino-
benzaldehyde 5b (1.0 g, 5.61 mmol) with malononitrile
(0.74 g, 11.21 mmol) and pyrrolidine (0.71 g, 11.12 mmol)
in absolute ethanol and refluxing for 9 h, furnished the
compound 6b. Yield: 1.14 g (56%), pale yellow solid, mp
198–2008C; IR (KBr): 3502, 3369 (NH2), 2198 (CN) cm21
;
1H NMR: d 1.19 (t, 6H, N (CH2–CH3)2), 1.96 and 3.78 (2t,
8H, J¼6.8 Hz, 30, 40-CH2 and N-CH2 pyrrolidine), 3.38 (q,
4H, N(CH2-CH3)2), 5.28 (bs, 2H, exchanged with D2O),
6.70 (d, 2H, J¼8.8 Hz), 7.42 (d, 2H, J¼8.8 Hz). 13C NMR:
d 12.55, 25.43, 44.22, 49.58, 80.21, 81.08, 110.59, 117.83,
119.13, 120.45, 130.44, 149.29, 158.34, 159.74, 162.01.
MS: m/z (%)¼360 (Mþ, 8), 359 (46), 345 (10), 344 (100),
316 (8), 233 (6), 70 (6). Anal. Calcd for C21H24N6 (360.46):
C, 69.97; H, 6.71; N, 23.31. Found: C, 70.14; H, 6.88; N,
23.61.
4.3.3. 3-Amino-2,4-dicyano-5-(2-pyridyl)-biphenyl (3c).
Following the above general procedure, treatment of 1-
phenyl-3-(2-pyridyl)-prop-2-en-1-one 1k (1 g, 4.78 mmol)
with malononitrile (0.64 g, 9.69 mmol) and pyrrolidine
(0.68 g, 9.57 mmol) in absolute ethanol and refluxing for
10 h, gave the compounds 2k (yield: 0.45 g (29%)) and 3c.
Yield: 0.75 g (53%), pale yellow solid, mp 264–2668C; IR
(KBr): 3479, 3382 (NH2), 2213 (CN), 1628, 1580, 1296,
1280, 791, 767, 700 cm21; 1H NMR (CDCl3, 400 MHz): d
5.45 (bs, 2H, NH2), 7.19 (s, 1H, C6-Ar H), 7.40–7.61 (m,
6H), 7.76–7.92 (m, 2H), 8.80 (d, 1H, J¼4.8 Hz); 13C NMR
(CDCl3, 100 MHz): d 92.58, 93.84, 114.53, 117.08, 121.86,
122.71, 126.95, 127.21, 127.94, 135.63, 136.12, 146.02,
148.03, 148.37, 152.80; 13C NMR-DEPT-135: d 119.65,
123.09, 124.23, 128.87, 129.70, 137.01, 149.94. MS (%):
m/z 296 (Mþ, 85), 295 (M-1, 22), 270 (27), 183 (23), 129
(43), 109 (42), 105 (30), 97 (29), 83 (61), 77 (20). Anal.
calcd for C19H12N4 (296.33): C, 77.01; H, 4.08; N, 18.91.
Found: C, 76.68, H, 3.95; N, 18.66.
4.4.3. 6-Amino-4-(4-methylphenyl)-2-(pyrrolidin-1-yl)-
pyridine-3,5-dicarbonitrile (6c). 4-Methylbenzaldehyde
5c (1.0 g, 8.33 mmol), malononitrile (1.09 g, 16.51 mmol)
and pyrrolidine (1.18 g, 16.62 mmol) in absolute ethanol on
refluxing for 9 h, furnished the compound 6c. Yield: 1.30 g
(52%), pale yellow solid, mp 278–2808C; IR (KBr): 3475,
1
3345 (NH2), 2206 (CN) cm21; H NMR: d 1.94 and 3.75
(2t, 8H, 30, 40 CH2 and N-CH2, pyrrolidine), 2.30 (s, 3H,
CH3), 5.31 (bs, 2H, exchanged with D2O), 7.26 (d, 2H,
J¼8.3 Hz), 7.38 (d, 2H, J¼8.3 Hz); 13C NMR: d 21.42,
25.36, 49.51, 80.96, 81.84, 116.88, 118.31, 128.39, 129.38,
132.01, 140.36, 157.60, 159.33, 162.18. 13C NMR (DEPT-
135): d 25.36(#), 49.51(#). MS: m/z (%)¼303 (Mþ, 92), 302
(100), 288 (50), 274 (64), 260 (54), 248 (8), 179 (10). Anal.
Calcd for C18H17N5 (303.36): C, 71.26; H, 5.64; N, 23.08.
Found: C, 71.48; H, 5.94; N, 23.31.
4.4. General procedure for the preparation of
polysubstituted pyridines 6a–f
To a solution of aromatic aldehyde 5 in absolute ethanol
(20 mL), malononitrile (2 equiv.) was added dropwise
followed by the addition of pyrrolidine (2 equiv.) at room
temperature. The reaction mixture was refluxed on a water
bath and monitored by TLC. After the disappearance of the
starting material, the solvent was removed under reduced
4.4.4. 6-Amino-4-(4-methoxyphenyl)-2-(pyrrolidin-1-yl)-
pyridine-3,5-dicarbonitrile (6d). 4-Methoxybenzaldehyde
5d (1.0 g, 7.35 mmol), malononitrile (0.97 g, 14.69 mmol)
and pyrrolidine (1.04 g, 14.64 mmol) in absolute ethanol on

V. Raghukumar et al. / Tetrahedron 59 (2003) 3761–3768
3767
refluxing for 9 h, furnished the compound 6d. Yield: 0.98 g
(41%), brownish yellow solid, mp 242–2448C; IR (KBr):
13C NMR: d 19.53, 25.89, 31.45, 32.28, 48.76, 66.97, 94.54,
110.64, 120.43, 127.34, 149.56, 158.26. MS: m/z (%)¼283
(Mþ, 8), 269 (14), 268 (100), 251 (8), 234 (6), 70 (10). Anal.
Calcd for C16H21N5 (283.37): C, 67.81; H, 7.47; N, 24.71.
Found: C, 67.79; H, 7.66; N, 24.90.
1
3444, 3340 (NH2), 2206 (CN) cm21; H NMR: d 1.97 and
3.79 (2t, 8H, J¼6.8 Hz, 30, 40-CH2 and N-CH2, pyrrolidine),
3.85 (s, 3H, OCH3), 5.34 (bs, 2H, exchanged with D2O),
7.01 (d, 2H, J¼8.8 Hz), 7.45 (d, 2H, J¼8.8 Hz). 13C NMR:
d 25.37, 49.54, 55.26, 80.88, 81.76, 114.08, 117.07, 118.48,
126.98, 130.15, 157.69, 159.39, 161.06, 161.72. MS: m/z
(%)¼319 (Mþ, 22), 318 (100), 303 (12), 290 (52), 276 (10),
259 (15), 247 (12), 173 (68), 158 (20), 143 (10), 127 (48), 99
(20), 93 (18), 70 (26), 55 (14). Anal. Calcd for C18H17N5O
(319.36): C, 67.69; H, 5.36; N, 21.93. Found: C, 67.97; H,
5.11; N, 22.14.
Acknowledgements
We wish to thank University Grants Commission—Special
Assistance Program for financial assistance. One of the
authors (D. T.) is thankful to CSIR, India for a fellowship.
P. R. and V. K. are thankful to DST for financial support.
4.4.5. 6-Amino-4-phenyl-2-(pyrrolidin-1-yl)-pyridine-
3,5-dicarbonitrile (6e). Following the above general
procedure, treatment of benzaldehyde 5e (1.0 g,
9.43 mmol) with malononitrile (1.24 g, 18.78 mmol) and
pyrrolidine (1.34 g, 18.87 mmol) in absolute ethanol and
refluxing for 7 h, furnished the compound 6e. Yield: 1.42 g
(52%), pale yellow solid, mp 238–2408C; IR (KBr): 3473,
References
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3321 (NH2), 2204 (CN) cm21; H NMR: d 1.96 and 3.70
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(2t, 8H, J¼6.6 Hz, 30, 40 CH2 and N-CH2, pyrrolidine), 5.36
(bs, 2H, exchanged with D2O), 7.44–7.51 (m, 5H, Ar-H).
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128.41, 128.65, 130.15, 134.92, 157.44, 159.27, 162.04.
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procedure, treatment of indole-3-carbaldehyde 5f (1.0 g,
7.5 mmol) with malononitrile (0.99 g, 15.03 mmol) and
pyrrolidine (1.06 g, 14.92 mmol) in absolute ethanol under
reflux for 9 h, furnished the compound 6f. Yield: 1.09 g
(41%), brownish yellow solid, mp 302–3048C; IR (KBr):
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8. Mercier, J.; Gavend, M.; Van Luv, V.; Dessaigne, S. Congr.
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3486, 3342 (NH2), 3221 (NH), and 2205 (CN) cm21; H
NMR: d 1.99 and 3.78 (2t, 8H, 30, 40-CH2 and N-CH2,
pyrrolidine), 6.49 (bs, 2H, exchanged with D2O), 7.14–7.65
(m, 5H, Ar-H), 11.50 (s, 1H). 13C NMR: d 25.15, 49.30,
80.36, 80.57, 109.87, 112.04, 117.65, 118.89, 119.81,
121.89, 124.97, 126.90, 131.91, 136.11, 155.02, 158.26,
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dihydro-1,6-naphthyridine-8-carbonitrile (8). To a sol-
ution of 4-methylpent-3-en-2-one 7 (1.0 g, 10.20 mmol) and
malononitrile (1.4 g, 20.30 mmol) in 20 mL of absolute
ethanol, pyrrolidine (1.44 g, 20.28 mmol) was added
dropwise at room temperature. The reaction mixture was
refluxed (17 h), until the disappearance of the starting
material, as monitored by TLC, and the solvent removed
under reduced pressure. The crude residue was purified by
column chromatography using silica gel and eluted with
hexane/chloroform (1:2) mixture to furnish the compound 8.
Yield: 0.92 g (32%), white solid, mp 198–2008C (EtOAc/
hexane); IR (KBr): 3492, 3352 (NH2), 2179 (CN) cm21; 1H
NMR: d 1.37 (s, 6H, gem-dimethyl), 1.80 (s, 3H, CH3), 1.91
and 3.68 (2t, 8H, 30, 40-CH2 and N-CH2, pyrrolidine), 4.21
(s, 1H), 4.74 (bs, 2H, exchanged with D2O), 5.91 (1H, bs).
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